Rejection quantity in kidney transplant recipients is associated with increasing intracellular interleukin-2 in CD8+ T-cells.

BACKGROUND: CD8+ T-cells and interleukin-2 play an important role during organ rejection in kidney transplant recipients. Numerous studies showed increased interleukin-2 levels during acute rejection. The aim of our study is to show an association between intracellular interleukin-2 in CD8+ T-cells and the incidence of those who underwent organ rejection in kidney transplant recipients. METHODS: 407 transplant recipients were included into this study. The rejection incidence was investigated from the patient records. White blood cells from recipients were separated using a ficoll gradient. The cells were double-gated (CD3+ and CD8+) for the analysis of cellular percentage for intracellular interleukin-2 with a flow cytometer. RESULTS: The percentage of CD8+ cells with detectable intracellular interleukin-2 was significantly higher in renal transplant recipients with a documented rejection compared to recipients without any history of rejection (9.06±0.50, N=133 vs. 4.28±0.24, N=274, p<0.0001, t-test). Further, there was a significant increase in patients with one (8.02±0.54, N=80, p<0.0001, t-test), two (10.40±1.17, N=33, p<0.0001, t-test) or three (11.82±1.58, N=18, p<0.0001, t-test) rejection events. CONCLUSIONS: Past studies showed, that during acute organ rejection intracellular interleukin-2 is increased in cytotoxic T-cells, supposed to be a marker for this event. We were able to show, that intracellular interleukin-2 in CD8+ T-cells is also increased after organ rejection. Furthermore it seems to depend on the quantity of rejection events. Further studies in recipients with increased intracellular interleukin-2 in cytotoxic CD8+ T-cells and documented history of organ rejection are needed to identify this as a possible risk factor for further rejection events.

Cholesterol-crystal embolism presenting with delayed graft function and impaired long-term function in renal transplant recipients: two case reports.

INTRODUCTION: Impaired renal function and/or pre-existing atherosclerosis in the deceased donor increase the risk of delayed graft function and impaired long-term renal function in kidney transplant recipients. CASE PRESENTATION: We report delayed graft function occurring simultaneously in two kidney transplant recipients, aged 57-years-old and 39-years-old, who received renal allografts from the same deceased donor. The 62-year-old donor died of cardiac arrest during an asthmatic state. Renal-allograft biopsies performed in both kidney recipients because of delayed graft function revealed cholesterol-crystal embolism. An empiric statin therapy in addition to low-dose acetylsalicylic acid was initiated. After 10 and 6 hemodialysis sessions every 48 hours, respectively, both renal allografts started to function. Glomerular filtration rates at discharge were 26 ml/min/1.73m(2) and 23.9 ml/min/1.73m(2), and remained stable in follow-up examinations. Possible donor and surgical procedure-dependent causes for cholesterol-crystal embolism are discussed. CONCLUSION: Cholesterol-crystal embolism should be considered as a cause for delayed graft function and long-term impaired renal allograft function, especially in the older donor population.

Prediction of acute renal allograft rejection by urinary monokine induced by IFN-gamma (MIG).

Early diagnosis of acute allograft rejection (AR) is still decisive for long-term renal allograft survival. The aim of this study was to define the role of the chemokine monokine induced by IFN-gamma (MIG) (CXCL9) and IFN-gamma-inducible protein 10 (IP-10) (CXCL10) as early markers of AR in renal transplantation (NTX). In a prospective study, 69 de novo renal transplant recipients were monitored and urine samples were collected after NTX for a median of 29 d. In pH-adjusted urine, MIG and IP-10 were determined by modified ELISA. AR was clinically diagnosed in 15 of 69 recipients and confirmed by biopsy in 14 of 15 AR patients (Banff classification). Corresponding to CXCR3-positive infiltrates in renal tissue, urinary MIG was elevated in 14 of 15 AR patients with a median of 2809 pg/ml (quartile 25% and 75% = 870 and 13,000; n = 15), being significantly (P < 0.0001) different from both nonrejecting allograft patients (NO-AR) (median, 25%, and 75%: 96, 1.0, and 161, n = 54) and healthy controls (median, 25%, and 75%: 144, 19, and 208, n = 13). Urinary MIG predicted AR with a sensitivity of 93% and a specificity of 89%. In AR and NO-AR groups, MIG values correlated well with IP-10 (P < 0.001). MIG values indicated both imminent rejection and response to successful antirejection therapy. MIG was not related to intercurrent infections or other causes for impairment of renal function. In a multivariate analysis, MIG correlated best (P < 0.001) with AR from all AR-associated parameters. In conclusion, urinary MIG serves as a very sensitive and specific predictor for AR, mirrors response to antirejection therapy, and thus may contribute to improved long-term renal allograft survival.

ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation.

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435C-->T polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435C-->T and 2677G-->T/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity (chi2 = 10.5; P = 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donor's ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donor's ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.